1. Field of the Invention
The present invention relates to new pharmaceutical compositions containing lignans for use in therapy. The present invention also relates to pharmaceutical combinations of lignans and TRAIL receptor agonists. In particular, the present invention concerns novel therapeutic and synergistic combinations of antineoplastic agents, comprising dibenzylbutyrolactone derivatives and TRAIL receptor agonists, which are useful in the treatment of cancer. The present invention also relates to the use of pharmaceutical combinations in treatment of cancer.
2. Description of Related Art
Prostate cancer is the most common type of cancer affecting men in the western world. Early prostate carcinomas that depend on androgen supply for their growth can metastasize as well as progress into castration-resistant prostate cancer (CRPC). While androgen deprivation therapy (ADT) remains as the first-line treatment of advanced prostate cancer, limited chemotherapeutic approaches are available and new drug targets are being investigated.
Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is common in cancer due to mutations in the key components of the pathway. PI3K activity is negatively regulated by the tumor suppressor, Phosphate and tensin homolog (PTEN), the function of which is commonly lost in prostate cancer. Activation of PI3K signaling may play a critical role in allowing prostate tumors to maintain continued proliferation in low-androgen environments, thereby promoting development of CRPC.
The PI3Ks are generally activated upon growth factor stimulation by receptor tyrosine kinases (RTKs) and mediate various cellular events such as cell proliferation, cell survival, cytoskeletal reorganization, migration, vesicular trafficking and metabolic control. The PI3Ks phosphorylate membrane inositol lipids generating the second messenger phosphatidylinositol (3,4,5)-triphosphate (PIP3), that recruits pleckstrin homology (PH) domain-containing proteins, such as Akt (PKB) kinases, to the cell membrane. Conformational changes and sequential phosphorylations result in Akt activation, translocation to the cytoplasm and phosphorylation of downstream targets. Several recent studies indicate that inhibition of the RTK/PI3K/Akt pathway with chemotherapeutic agents is an attractive strategy to treat prostate cancers.
In connection with the present invention, structure-activity analysis of lignan polyphenols has been carried out with the aim of evaluating cancer cell specific sensitization to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), a death ligand that has ability to induce tumor-specific cell death.
Lignans are a group of plant-derived polyphenolic compounds, some of which have the capability to inhibit Akt signaling in prostate cancer cells. Lignans act as antioxidants and some lignan types are categorized as phytoestrogens, naturally occurring estrogen-like chemicals.
Lignans are formed primarily from oxidative coupling of two phenylpropane moieties at their beta-carbon atoms. Further oxidations and ring formation reactions result in different classes of lignans with a wide structural diversity. The butyrolactone ring, which is the main structural feature of dibenzylbutyrolactone lignans, is one of the most abundant structural moieties in naturally occurring lignans.
Dibenzylbutyrolactone lignans such as hydroxymatairesinol, matairesinol, arctigenin and enterolactone have been widely studied due to their biological effects. Also, substantial health benefits may be associated with lignan-rich diet, including prevention of cardiovascular disease and reduced risk of hormone-dependent cancer. A recent meta-analysis of several studies revealed that high lignan exposure might indeed correlate with a reduced breast cancer risk in postmenopausal women.
Inhibition of Akt signaling by the lignan matairesinol (MAT) has earlier been shown to sensitize prostate cancer cells to TRAIL-induced apoptosis (Peuhu et al. 2010). However, efficacy of TRAIL treatment should further be improved in order to effectively eliminate prostate cancer cells.
Endogenous TRAIL is widely expressed in hematopoietic cells with an emerging role in maintenance of self-tolerance, but also as a mechanism of immune surveillance against virally infected or malignant cells. In fact, TRAIL can specifically trigger apoptosis in vivo in tumors without killing non-transformed cells. Employment of TRAIL in cancer therapy has gained a great deal of attention, and early results from phase I/II clinical trials with recombinant TRAIL or agonistic anti-DR4 and anti-DR5 antibodies suggest that TRAIL receptor agonists may exert anticancer activity also in humans.
However, TRAIL-resistance has been reported in these clinical studies, as well as in many primary tumor cells derived from human breast, lung and colon tumors, suggesting that combination with other chemotherapeutic treatments is likely to be required for successful TRAIL-therapy. Thus, new and carefully chosen combinations to TRAIL-therapy are needed.